Intermittent Claudication

Peripheral arterial disease comprises those disorders that limit blood flow to the distal limbs.  The most frequent cause of limb artery obstruction is atherosclerosis.  The principal symptom of peripheral arterial disease is intermittent claudication.[1]  Intermittent claudication is pain in the legs that occurs with walking and resolves with rest.  Claudication comes from the Latin word "claudicare," which means to limp.

Patients with intermittent claudication can usually walk only short distances and are therefore often unable to perform their daily activities.  Patients can typically walk only one-half block to four blocks before they must stop and rest.[2]  Their normal walking speed is about 1-2 miles per hour, with age-matched controls walking 3.3 miles per hour.  About one-third of patients indicate that they have difficulty walking around their homes, and two-thirds indicate that they have difficulty walking 150 feet,[2] whereas age-matched controls are essentially unlimited in the distance they can walk.

Decription of the Disease by Physician and Patient
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This limited ability to walk makes intermittent claudication a debilitating condition, because patients are unable to perform daily occupational, personal, and social activities.  This disability is particularly detrimental, since both leisure and work activities are often severely curtailed for the sufferers.[3]  Examples of such activities are walking at work, shopping, house cleaning, leisure walks, dancing, hiking, and travel within the airport.  See Table 1 for other examples. 

Table 1: Examples of the impact that intermittent claudication might have on a person ability to perform daily occupational, personal, and social activities. 

·        Activities with grandchildren, such as going to the zoo or park, may be curtailed.

·        Going to the mall and grocery store for clothing and food can be difficult.

·        Housecleaning can be difficult for those who cannot be on their feet for more than a few minutes.

·        A handicapped sticker may be necessary to be able to park close to the bank, post office, grocery store, and other locations.

·        Golfers may need to ride in a golf cart versus walking the course.

·        Those who love to dance may not be able to as they once did.

·        Those who always hiked or walked for pleasure have gradually had to shorten their distances.

·        Travel is more difficult (e.g., wheelchairs and motorized transportation at airports must be prearranged; hotel arrangements must be made so as to avoid stairs and long walks from parking lots; "seeing the sights" is restricted to places with easy access.

Effect of Disease on Lifestyle
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Epidemiology 

Peripheral arterial disease affects approximately 8 million individuals in the United States.[4,5]  The incidence of intermittent claudication, the primary symptom of peripheral arterial disease, increases sharply in late middle age, with higher rates in men than in women.[4]  In addition, intermittent claudication develops earlier in men than in women.[6]  Figure 1 shows that the prevalence of intermittent claudications increases with age from 1.1% in people under age 40 to 5.2% in people over age 69.[7,8]

Figure 1: Prevalence of intermittent claudication by age.[7,8]
 

 

About three-quarters of patients with intermittent claudication remain symptomatically stable over a 5-year period.  The natural history of peripheral arterial disease indicates that in 16% of patients, claudication worsens, 7% require bypass surgery, and 4% require amputation.[2,9]

Risk Factors 

The risk factors associated with the development of peripheral atherosclerosis are similar to those associated with the development of coronary atherosclerosis.

Risk factors for peripheral arterial disease should be identified and treated to reduce the likelihood or progression of atherosclerosis (Table 2).  These factors include cigarette smoking,[10,11,12,8] dyslipidemia,[10,8] hypertension,[10,8] diabetes mellitus,[12,13,14,15,8], and hyperhomocysteinemia.[16]  Other risk factors are age, family history, and obesity.  

Table 2: Risk Factors for Intermittent Claudication

Risk Factor

Increased Risk

Cigarette smoking

2- to 7-fold

Dyslipidemia

2-fold

Hypertension

2-fold*

Diabetes mellitus

3-fold

Hyperhomocysteinemia

3-fold

* = Increased risk in women is 4-fold.

Successful smoking cessation has major effects on survival in patients with intermittent claudication.  The 5-year mortality rate for patients with intermittent claudication who continue to smoke may be as high as 40-50%.[17]  In contrast, smoking cessation in this population is associated with markedly decreased rates of myocardial infarction (11% vs. 53% after 10 years) and results in an improvement in survival rate (82% vs. 46% after 10 years).[18]  Continued cigarette smoking increases the risk of progression from stable intermittent claudication to severe limb ischemia and amputation.  Rest pain has been shown to develop over 7 years in as many as 16% of patients with intermittent claudication who continued to smoke cigarettes, whereas rest pain was exceedingly rare in patients who stopped smoking.[18]

Causes of Intermittent Claudication
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Clinical Presentation

The pathology of atherosclerosis affecting the arteries in the limbs is similar to that affecting other major arteries (see Figures 2 & 3).  Intermittent claudication is described as discomfort, pain, fatigue, numbness, or heaviness that is felt in the affected extremity during walking and that resolves after a few minutes of resting.  From a functional standpoint, intermittent claudication is the primary symptom that limits normal activity in patients with peripheral arterial disease.[1,8]

In patients with intermittent claudication, a hemodynamically significant stenosis prevents blood flow augmentation during walking.  The increased pressure gradient that develops across the stenosis causes a reduction in the perfusion pressure to the working muscle.  As ischemia develops, local vasodilation and further reduction in arterial perfusion pressure occur.  This results in a metabolic environment in the leg muscles in which the demand for oxygenated blood exceeds the supply.

 

Figure 2: Normal artery
 
 
 

Figure 3: Abnormal artery

 

 

The location of the symptoms depends on the site of the stenosis (figure 4).  Buttock, hip or thigh claudication may develop in cases of proximal arterial occlusive disease involving the aorta or iliac arteries.  Involvement of the femoral or popliteal arteries typically causes calf pain.  Tibial and peroneal artery stenoses may cause foot pain. 

Figure 4: Site of obstruction resulting in intermittent claudication
 
 
 
Figure 5: Natural history of peripheral arterial disease.[8]
 

 

Diagnosis
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Diagnosis

The diagnosis of peripheral arterial disease is based primarily on the patient's history and physical examination.  Patient history is an important step in the diagnostic process.  If the patient answers yes to any of these question they may have intermittent claudication.

·        Do you get pain in either leg when walking?

·        Does this pain only begin when you are walking?

·        Do you get this pain in your calf (or calves)?

·        Do you get leg pain when you hurry or walk uphill?

·        Do you get leg pain walking at an ordinary pace on level ground?

·        Does the leg pain always continue unless you stop walking?

 If the patient answers yes to any of these questions, they may have intermittent claudication. 

 When the patient does see their physician, most physician will perform a complete physical exam with special emphasis on the vascular system to ascertain the presence of systemic atherosclerosis.  This exam may include: 

·        check pulses, beginning with the carotid, brachial, and radial arteries

·        palpate and auscultate the abdomen for a possible aneurysm or bruits

·        examine femoral pulses

·        examine popliteal pulses with the patient supine, knees bent

·        check dorsalis pedis pulses

·        examine feet for thin, atrophic skin, toenail thickening, and cracks between toes

In addition, some will perform a noninvasive vascular test to determine disease severity and location.  Some of the test that might be done are:

 ·        Doppler ankle-brachial index (ABI)

·        segmental pressures

·        pulse volume recording waveforms

·        Doppler waveform analysis, duplex imaging, exercise Doppler studies

·        treadmill exercise testing with treadmill set at an angle

One of the most commonly used noninvasive vascular test is the ABI.  The ABI is an objective assessment of disease severity can be made by determining the ankle-brachial index, the ratio of systolic blood pressure in the ankle to that in the arm.  The Doppler ABI may be measured in the office using a blood pressure cuff and Doppler ultrasound (see figure 6 and 7).

Figure 6: Measurement of a ABI.
 
Figure 7: Tools used in the measurement of a ABI. 

 The following steps are used with the Doppler ABI test: 

Step 1  The brachial (arm) systolic pressures is measured in both arms.

Step 2  The blood pressure cuff is place around the ankle to obtain dorsalis pedis and posterior tibial arterial systolic pressures.

Step 3  Divide the highest ankle pressure by the highest brachial pressure to arrive at the ABI (normal value >0.95)

ABI = Ankle Systolic Blood Pressure / Arm Systolic Blood Pressure

Calculation of the ABI is an objective, sensitive, highly specific and predictive tool used primarily to corroborate the diagnosis of intermittent claudication. Measurement of the pressures in the ankles and arms is performed using a Doppler stethoscope, sphygmomanometer and conventional blood pressure cuffs. Normally, blood pressure in the legs and arms is similar. In patients with peripheral arterial disease, the arterial pressure in the leg distal to a stenosis is decreased. Thus, a ratio of ankle: brachial pressures is >0.95 in normal individuals and generally 0.90 with peripheral arterial disease.

Current Treatment Options for Intermittent Claudication

The primary treatment objective for patients with intermittent claudication is to improve their pain-free and maximal walking distances.  Treatment options include risk factor reduction (Table 3), exercise rehabilitation, and pharmacologic therapy; surgical revascularization may be necessary if other therapies fail.

Table 3: Risk Factor Reduction 

·        Management of lipid abnormalities

·        Management of hypertension

·        Management of diabetes mellitus

·        Treatment of hyperhomocysteinemia

·        Cessation of smoking

·        Increased physical activity

Exercise Rehabilitation

Exercise rehabilitation has been shown to improve the functional status of patients with intermittent claudication.[19,20,8]  The optimal exercise is walking: where the patients walk to near-maximal pain, then rests until the pain subsides, and repeats this walking/resting cycle for at least 30 minutes per session.  The recommended program is at least 3 sessions per week for at least 6 months.[21]

Pharmacologic Therapy 

There are only two medications indicated for treating the symptoms of intermittent claudication: Pentoxifylline (Trental®) and cilostazol (Pletal®).  Pentoxifylline was approved in 1984 and cilostazol was approved in 1999. 

Other agents that have been used in the treatment of intermittent claudication have included ticlopidine, vasodilators such as alpha blockers, calcium channel blockers (verapamil), and angiotensin-converting enzyme inhibitors.  Aminophylline, Vitamin E, ginkgo biloba, and isoxuprine among others.[8,22,23]

Treatment
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General Benefit Discussion #2
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Pentoxifylline 

Pentoxifylline is a methylxanthine derivative approved for the treatment of intermittent claudication.  It has also been used to treat a number of other conditions including cerebrovascular accident, contact dermatitis, macular degeneration, adjunctive treatment of ulcers of the lower limb, caused by ischemic, and acquired immunodeficiency syndrome.

Figure 8: Structure of pentoxifylline.
 
molecular structure

Pentoxifylline's ability to improve blood flow to the peripheral vasculature is unrelated to vasodilation.  The original mechanism of action centered on the concept of a hemorheologic effect on blood cells.  Pentoxifylline caused a decreased blood viscosity, inhibition of platelet aggregation, enhancement of erythrocyte flexibility, and a decrease in fibrinogen concentration.  The most important of these effects was the alteration of erythrocyte flexibility.  The increase in erythrocyte flexibility was a result of the drug's ability to increase the amount of phosphoprotiens in the erythrocyte.  This phosphorylation of the erythrocyte's membrane proteins occurs because pentoxfylline facilitates magnesium-dependent protein kinase activity and inhibits the calcium-dependent phosphoprotein phosphatase and transglutaminase. 

Efficacy 

Studies of pentoxifylline efficacy in peripheral vascular disease involved both controlled and uncontrolled clinical trials, all of which indicated that pentoxifylline was effective in some patients with peripheral occlusive vascular disease.  Newer studies, have not been able to confirm these results. 

Most of the originally studies were controlled clinical trials conducted against a placebo control.  Studies comparing pentoxifylline with the traditional vasodilators are very limited.  The results of these studies indicate that pentoxifylline is an effective agent in the treatment of intermittent claudication.

 Table 4: Summary of pentoxifylline studies in the area of peripheral vascular disease.

Study Design

# Patients

Dosage

Duration of therapy

Results

References

DBPC

128

Pentox 400 mg TID

P TID

6 months

62% improvement with pentoxifylline

15% improvement with placebo

24

DB

47

Pentox 400 mg TID

N 3 mg TID

8 weeks

47% improvement with pentoxifylline

1% improvement with nylidrin

25

Open

40

Pentox 400-800 BID

4 weeks

95% improvement

26

Open

73

Pentox 400 mg BID-TID

2-3 months

76% improvement in lower extremities

83% improvement in upper limbs

27

Open

152

Pentox 400 mg BID, initially given IV

10 weeks

75% improvement

28

Open

14

Pentox 400 mg TID

6 months

walking distance increased by twice that achieved in exercise program

29

Open

67

Pentox 400 mg BID-TID

8 weeks

75% improvement

30

DBPC

40

Pentox 400 mg TID

P TID

4 weeks

88% improvement with pentoxifylline

52% improvement with placebo

31

DBPC

40

Pentox 400 mg TID

P TID

6-8 weeks

70% improvement with pentoxifylline

5% improvement with placebo

32

DBPC

50

Pentox 800 mg/d

P

4-6 weeks

84% improvement with pentoxifylline

17% improvement with placebo

33

DBPC

26

Pentox 1200 mg/d

P

6 months

89% improvement with pentoxifylline

27% improvement with placebo

34

 

In the pentoxifylline and nylidrin study, the drugs were administered for eight weeks in a randomized double-blind method.  The patients in this study had occlusive peripheral vascular disease of the lower extremities (Fontaine state II or III).  Forty-seven treatable patients completed the study; 23 pentoxifylline patients (400 mg three times daily for 8 weeks) and 24 nylidrin patients (3 mg three times daily for 8 weeks).  Both groups showed an improvement in walking performance (walking time and distance) at four weeks and eight weeks.  However, pentoxifylline was the only one to show a significant increase.  At the end of four weeks, the pentoxifylline group showed a 47.1% increase over baseline compared with a 5.6% increase in the nylidrin group (p=0.024).  At the end of eight weeks, the pentoxifylline group showed a 47% increase compared with the 1% observed with nylidrin therapy (p=0.016).[25] 

In addition to walking performance, the study used acral plethysmography prior to treatment and at the completion of the study to evaluate the patients' extremities.  In the pentoxifylline-treated patients, the acral plethysmography was improved by 52% and either no effect or wrosening of their condition in 48%.  In the nylidrin-treated patients these figures were 25% and 75%. 

The adverse effects most commonly associated with pentoxifylline therapy involve the gastrointestinal and central nervous system.  The gastrointestinal adverse effects include dyspepsia, nausea, and vomiting.  The central nervous system adverse effects include dizziness, headache, and tremor.  The incidence of adverse effects are transient and dose related.[24,25,27] 

Since pentoxifylline decreases blood viscosity and prevents platelet aggregation, care should be used in patients receiving anticoagulants and antiplatelet medications.  Also, the patient will not be able to donate blood or plasma while taking the pentoxifylline.

The recommended starting dose of pentoxifylline is 400 mg three times daily.  Clinical effects are usually observed by the second or fourth week of therapy.  Patients who do not show an improvement should continue to receive drug for an additional four weeks to assess the drug's efficacy.  

Patient Counseling 

Pentoxifylline is used to improve blood flow and blood circulation in the legs.  It may take several weeks for the medicine to make a difference in how far you can walk without pain or discomfort.  In order for the pentoxifylline to work best, you must take it on a continuous basis along with the exercise program that has been suggested by your physician.

Do not drive, operate machinery, or do anything else that could be dangerous until you know how this medication effects you.  Using this medicine along with alcohol or other medications that can cause sedation may lessen your ability to drive or to perform other potentially dangerous tasks. 

Potential side effects that may occur while taking pentoxifylline are nausea, stomach discomfort, dizziness, headache, or flushing.  Most of these side effects will go away during treatment, but if they continue or are bothersome you should contact your prescriber.  If you experience a rash or vomiting, you should check with your prescriber immediately. 

If you are female and plan on becoming pregnant, you should discuss the potential impact of this medication on your pregnancy or fetus. 

If you are breast feeding, you need to discuss whether the pentoxifylline or the breast-feeding should be discontinued since pentoxifylline is excreted in breast milk. 

Pentoxifylline is available only as an controlled release tablet.  These tablets should not be crushed, chewed, or broken before swallowing. The drug should be taken with food or milk will to improve its gastrointestinal tolerability. 

If you miss a dose take it as soon as possible.  If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. 

Copy of Trental ® product labeling.

Cilostazol 

Cilostazol (Pletal™ - Otsuka America Pharmaceutical, Inc./Pharmacia) is approved for use in the treatment of intermittent claudication.[35]  Other potential use of cilostazol include the treatment of post-stroke syndrome, the prevention of recurrent stroke, prevention of thrombosis and restenosis after stent placement, prevention of restenosis after angioplasty and the prevention of graft occlusion.[36,37,38,39,40,41,42,43,44]

 

Figure 9: Structure of cilostazol
 

Clinical Pharmacology  

Cilostazol is a potent and selective inhibitor of cGMP-inhibited cAMP phosphodiesterase (PDE type 3, PDE3).[35,45,46,47] Cilostazol inhibits platelet aggregation, including platelet aggregation induced by stress, ADP, collagen, arachidonic acid and epinephrine.[46,48,49,50,51,52]  Anti-aggregatory effects are observed within 6 hours of administration of a single dose.  Platelet aggregability almost completely recovers within 48 hours after drug withdrawal, with no effects observed at 96 hours after withdrawal.  Recovery correlates with plasma concentrations of cilostazol.[50]  In vitro and in vivo studies suggest cilostazol is a more potent antiplatelet agent than aspirin, dipyridamole, ticlopidine or pentoxifylline.[48,49,52,36] The anti-aggregatory effects of cilostazol are potentiated by endothelium-derived prostacyclin.[53]  When administered with a prostacyclin analog, however, an additive increase in intracellular cAMP levels was observed, but not excessive vasodilation or additive or synergistic inhibition of platelet function.[45]  In animal studies, administration of cilostazol prevented reocclusion after coronary thrombolysis with alteplase and heparin.[54]  

In addition to platelet effects, cilostazol inhibits PDE3 in the blood vessel and produces vasodilation by increased cAMP levels in the vascular smooth muscle cells.[35,38,55,56,57] There was an increase in peripheral blood flow in patients with Type 2 diabetes, as observed by an increase in digital skin temperatures and an increase in the cross-section area of the dorsalis pedis artery and the blood flow index.[58,59] There was increased blood flow in the lower extremities in patients treated with cilostazol who had chronic arterial occlusion in the extremities (arteriosclerosis obliterans or thromboangiitis obliterans).[60,61,62]  Improved cerebral blood flow was observed in patients with cerebral infarction.[63] 

Cilostazol also exerts an antiproliferative effect that may prevent restenosis and reduce progression of arteriosclerosis.[38]  Cilostazol may prevent the initiation and progression of arteriosclerosis by inhibiting platelet-derived growth factor production in vascular endothelial cells, suppressing the expression of heparin-binding epidermal growth factor in smooth muscle cells and macrophages or by augmenting endogenous nitric oxide production by vascular smooth muscle cells.[47,64,65]  Daily administration in patients with diabetes reduced endothelial damage, which may lessen the risk of vascular complications.[66,67]  An inhibitory effect on intimal proliferation and reduced restenosis has been observed following arthrectomy with cilostazol therapy.[36] 

Cilostazol has positive chronotropic, bronchodilatory, bronchoprotective and renal protective effects.[55,68,69] Cilostazol had positive chronotropic effects in patients with bradyarrhythmias including bradycardiac atrial fibrillation and sick sinus syndrome.[68]  In patients with Type 2 diabetes and microalbuminuria, administration of cilostazol 100 mg daily for 3 months affected urinary albumin index with a reduction in renal production of thromboxane B2 and an increase in the ratio of 6-keto prostaglandin F1a/thromboxane B 2.[70]  Cilostazol had no effects on blood glucose and hemoglobin A1c.[70]  Triglycerides were decreased by 15%, while increases were seen in cholesterol by 0.5%, HDL by 9.5%, HDL2 by 56%, HDL3 by 3%, LDL by 1% and ApoA1 by 6.3%.[71] Larger differences in lipid profile have been reported in other studies: 69% decrease in triglycerides, 9% decrease in total cholesterol, 6% decrease in LDL and 7% increase in HDL.[72] 

Pharmacokinetics

Peak plasma concentrations occur 2 to 4 hours after oral administration.[50,56,73,74,75]  Absorption appears unaffected by administration with food.[73]  Administration with a high fat meal increase the peak serum concentration by 90% and the area-under-the-curve by 25%.[76]  Peak anti-aggregatory effects are observed at 6 hours after oral administration.[50]  With regular administration, effects correlate well with plasma concentration--peak effects with peak levels and reduced effects with declining levels were observed.[50] 

Cilostazol is extensively plasma protein bound, primarily to albumin.[56]  A trend toward increasing free fraction of cilostazol with age has been observed, correlating with a reduction in plasma albumin concentration with age, but this finding should not be clinically significant.[56]  The mean terminal half-life is 11 to 26 hours, although it has not been well characterized due to apparent biphasic elimination.[56,73,74,77,75]  The distribution half-life is 2 to 3 hours, and the terminal half-life of 18 to 26 hours.[73,74,77]  Cilostazol is metabolized primarily by hydroxylation to numerous metabolites (3,4dehydro-cilostazol (OPC-13015) and 4'-trans-hydroxy-cilostazol (OPC-13213)), which have half-lives comparable to the parent drug.[56]  Unchanged cilostazol is not detected in the urine.[74,77,75] 

Pharmacokinetics have not varied with age or by gender.[56] 

Clinical Efficacy 

The efficacy of these agents is now determined by change in maximal walking distance (also known as the absolute claudication distance) using treadmill testing, quality of life questionnaire, and walking improvement questionnaires.  Prior to the treadmill test the patients are instructed to walk to the point that normally makes them stop because of pain and discomfort.  The maximal walking distance measurement represents a clinically relevant assessment of the symptoms experienced by patients in their day-to-day living. 

Also recorded during the treadmill testing was the pain-free walking distance (also known as the initial claudication distance).  The pain-free walking distance is the distance walked until the patient first feels leg pain. 

Treadmill testing creates a metabolic environment in the leg muscles in which the demand for oxygenated blood exceeds the supply.  Two treadmill tests commonly used in research and clinical practice were used to evaluate the maximal walking distance in the clinical trials.  

Treadmill walking can be translated into a work rate or measurement of energy expenditure, e.g., metabolic equivalent (MET).  One MET is the energy expended at rest.  The normal walking speed for this population is about 1-2 miles per hour on level ground.  This walking speed translates to about 2-2.5 METS.  The treadmill tests used in the clinical trials required that patients walk at an intensity 2 to 3 times more difficult than other normal walking intensity. 

The results of 8 phase III trials enrolling 2,702 patients were submitted to the FDA in the cilostazol application for approval for intermittent claudication.[78]  Overall, cilostazol efficacy is greater than placebo and at least comparable to pentoxifylline.[78]  

Placebo-controlled studies indicate that cilostazol is better than placebo in the treatment of intermittent claudication.  Cilostazol 50 mg or 100 mg was compared to placebo.  Patients walked at a steady 2 miles per hour up a 12% grade.  Those patients taking the cilostazol 100 mg dose had a 381% improvement in walking distance, walking an estimated 1.3 blocks further.  Those taking the 50 mg dose had a 150% improvement.[78] 

The results of 1 multicenter, randomized, double-blind, placebo controlled study enrolling 239 patients 41 to 91 years of age with intermittent claudication secondary to peripheral arterial occlusive disease were published.  Patients received either cilostazol 100 mg twice daily or placebo for 16 weeks.  Treadmill testing was conducted with a variable-grade, constant speed treadmill which begins with no incline and a speed of 3.2 km/hr, and the incline increases by 3.5% every 3 minutes.  Patients treated with cilostazol had greater improvement than the placebo-treated patients in absolute claudication distance assessed via treadmill testing at the end of the 12-hour dosing interval at weeks 8, 12 and 16.  Walking distances were also improved with treadmill testing performed 3 to 4 hours after dosing.  At week-16, cilostazol-treated patients had a 96.4 meter (47%) increase in absolute claudication distance compared with a 31.4 meter (12%) increase in the placebo group (p<0.001).  Time to absolute claudication increased from 265 seconds at baseline to 372 seconds in the cilostazol group, but was unchanged in the placebo group.  In the Walking Impairment Questionnaire, improvements were reported in walking speed and specific measures of walking difficulty.  Greater improvement in overall functional status (assessed with the SF-36) was also observed in the cilostazol-treated patients.  Among patients treated with cilostazol, 55.5% judged their condition as better or much better, compared to 35% of placebo-treated patients.  The investigators judged 47% of the cilostazol-treated patients to be better or much better compared to 32.5% of the placebo-treated patients.[79] 

Eighty-one patients with stable symptoms of intermittent claudication were enrolled in a placebo-controlled study.  Their symptoms had to be present for at least 6 months and unchanged within the past 3 months.  Patients were excluded if they had limb-threatening chronic limb ischemia, lower-extremity surgical or endovascular arterial reconstruction or sympathectomy in the preceding 6 months, uncontrolled hypertension, inability to complete the treadmill walking test for reasons other than claudication, recent myocardial infarction, recent deep vein thrombosis, severe concomitant diseases, substance abuse or gross obesity.  Patients were also excluded if they were taking antiplatelet agents, anticoagulants, vasoactive agents, hemorrhagical agents, or nonsteroidal antiinflammatory drugs (except acetaminophen and diclofenac sodium).  All patients went through a 2-week baseline period for stabilization of their other medications and then a 2 to 4 week single-blind placebo lead-in phase.  If the treadmill tests were stable, the patients were randomized to receive cilostazol 200 mg or placebo twice daily for 12 weeks.  Treatment center and the patient’s use of calcium channel blocker stratified randomization with a 2:1 assignment to cilostazol therapy.  The treadmill test was conducted at a constant 2 mile/hour speed at a fixed incline of 12.5%.  In addition, brachial, anterior tibial and posterior tibial artery systolic pressure was measured using continuous-wave Doppler ultrasound and cuff occlusion.  Sixty-six patients complete the study, with 18.5% in both groups being withdrawn or excluded after randomization.  The primary end point of the study was a change in walking distance.  After 12 weeks, the pain-free walking distance improved by 58% with cilostazol and 8.9% with placebo, and the maximum walking distance was improved by 63% with cilostazol and 9.8% with placebo.  The differences between the 2 groups were not statistically different until after 12 weeks in both the intention-to-treat group and those completing the study.  Those treated with cilostazol rated their improvement better than those treated with placebo.  The same trend was seen in the physician’s assessment of the patient’s improvement.[72] 

The results of 8 phase III placebo-controlled, double-blind studies enrolled 2,274 patients with intermittent claudication.  The studies ranged in duration from 12 to 24 weeks.  The best results were achieved with cilostazol 100 mg twice daily, but the cilostazol 50 mg twice daily was also better than placebo.  Both doses increased the distance before claudication pain and the maximum walking distance.[35,80]  

Table 5: Patient demographics [35]

Characteristic

Cilostazol 50 mg BID
(n=303)

Cilostazole 100 mg BID
(n=998)

Placebo
(n=973)

Mean age (years)

64.2

65.2

65.4

Mean Resting ankle/brachial index

0.62

0.64

0.64

% Men

76%

76%

77%

% Caucasian

85%

91%

89%

% of Patients with a history of:

     

Diabetes

29%

25%

25%

Hypertension

57%

60%

60%

Stable angina

12%

18%

19%

Myocardial infarct

25%

20%

22%

Transient ischemia attack

2%

7%

8%

Stroke

5%

3%

5%

Arrhythmia

9%

12%

11%

Current cigarette smoking

41%

40%

41%

Previous cigarette smoking

51%

52%

51%

 

 Table 6: Exclusionary criteria used in the studies.[35] 

·        Age < 40 years
·        Critical limb ischemia
·        Blood pressure >200/100 mmHg
·        Any history of clinically significant bleeding tendencies
·        Unstable angina pectoris
·        Lower extremity arterial reparative surgery including endovascular procedures, within the 3 months prior to randomization
·        MI, PCTA, or CABG within the 6 months prior to randomization
·        Symptomatic cardiac arrhythmias

·        Termination of treadmill walking test for reasons unrelated to intermittent claudication (e.g., angina, dyspnea, orthopedic problems)

·        Women of childbearing potential not using reliable birth control

·        Previous entry in other cilostazol studies

·        Diagnosed peripheral arterial disease for < 6 months and not stable for 3 months prior to randomization

·        Ankle/brachial index > 0.90

·        < 10 mmHg drop in ankle pressure within 1 minute following treadmill test

·        Use of medications with a significant anticoagulant or hemorrheologic modifying component (except acetaminophen, aspirin up to 81 mg/day, and ibuprofen up to 1200 mg/day)

Overall, cilostazol efficacy is greater than placebo and at least comparable to pentoxifylline.[35,81]  Comparisons with pentoxifylline indicated that patients treated with cilostazol were able to walk further than those treated with pentoxifylline or placebo.  Cilostazol 100 mg twice daily, pentoxifylline 400 mg 3 times daily and placebo were compared for 24 weeks.  Pentoxifylline was no more effective than placebo.  The pain-free walking distance increased by 98.3% with cilostazol, 68.4% with pentoxifylline and 55.1% with placebo.  The mean walking distance increased by 53.9% with cilostazol, 30.4% with pentoxifylline and 33.5% with placebo.  After 24 weeks of treatment, cilostazol-treated patients were able to walk 107.3 meters longer, and the pentoxifylline group was able to walk 64.4 meters longer.[81]  However, the FDA has required the company to conduct a 1-year comparison study with placebo and pentoxifylline in the management of intermittent claudication.  This study is intended to gather additional data on cilostazol’s long-term safety and effectiveness. This treatment group is required to include sufficient number of patients who are also receiving clopidogrel.[82,80] 

Other Potential Uses 

Clinical efficacy with cilostazol therapy showed the drug to be effective in 26 patients with peripheral arterial disorders (Takayasu’s arteritis, Buerger’s disease, arteriosclerosis obliterans) treated with cilostazol 200 mg/day for at least 3 months.  Improvement was reported by 13 patients, including healing of ischemic ulcers, increases in walking distance and/or improvement of ischemic pain.[83] 

The effects of cilostazol on restenosis after coronary arthrectomy were evaluated in a randomized study enrolling 41 patients with stable angina who were candidates for directional coronary arthrectomy.  Patients received either cilostazol 100 mg twice daily or aspirin 250 mg once daily.  At 6-month follow-up, the cilostazol group had a larger minimal lumen diameter, smaller percent diameter stenosis and smaller percent plaque area.  The restenosis rate was 26% in the aspirin group compared to zero in the cilostazol group.[36]  The effects of cilostazol on restenosis after percutaneous transluminal coronary angioplasty were evaluated in comparison with other antiplatelet agents or warfarin.  Following successful PTCA, patients received either cilostazol alone 200 mg/day (46 patients) or other antiplatelet agents (aspirin, ticlopidine, aspirin and ticlopidine) or warfarin (56 patients) and were followed for 3 to 6 months.  The lesion non-progression rate, defined as the incidence of lesions with either no change or regression of coronary stenosis at the PTCA site, was greater in the cilostazol group than in the control group (37% vs 16%, p<0.05).[37] Cilostazol was compared to aspirin or ticlopidine in 68 patients following PTCA in another study.  Patients received either cilostazol 100 mg/day or aspirin 81 mg/day or ticlopidine 300 mg/day.  Restenosis occurred less frequently in the cilostazol-treated patients.  At PTCA sites, minimal lumen diameter was much greater in the cilostazol-treated patients than in the patients treated with aspirin or ticlopidine.[38] 

Cilostazol was also evaluated in the prevention of stent thrombosis.  Cilostazol and aspirin were compared in 70 patients with 82 lesions who underwent Palmaz-Schatz stent implantation.  Patients received either cilostazol 200 mg/day or aspirin 81 mg/day.  Subacute thrombosis occurred in 1 aspirin-treated patient and none of the cilostazol-treated patients.  No acute complications (death, emergent coronary artery bypass grafting or hemorrhagic complications) or adverse effects occurred in either group.  The minimal lumen diameter was greater in the cilostazol group.  The restenosis rate was 26.8% in the aspirin group compared to 8.6% in the cilostazol group.[39]  In another study, cilostazol 100 mg twice daily and aspirin 81 mg 3 times daily were administered concurrently to 71 patients with 84 lesions following angiographic confirmation or optimal implantation of a Palmaz-Schatz stent.  There were no deaths, Q-wave myocardial infarctions, stent thrombosis, coronary bypass surgery or serious side effects during the 1-month follow-up period.[40]  

Thirty patients who had undergone an aortoiliac bypass graft because of arteriosclerosis or aortic aneurysm received either a knitted Dacron graft and ticlopidine 300 mg/d for 24 months, a Gore-Tex graft and treatment with ticlopidine 300 mg/d for 24 months or a Gore-Tex graft and cilostazol 200 mg/d for at least 2 months.  Early graft occlusion did not occur in any treatment group; late graft occlusion (24 + months) occurred in 2 patients with Dacron grafts treated with ticlopidine, 1 patient with a Gore-Tex graft treated with ticlopidine and none of the cilostazol-treated patients. However, because of the small number of patients in this study, an accurate comparison of agents could not be made.  The platelet activation index was lowest in the cilostazol-treated patients.[41]  Cilostazol was also compared with warfarin in a retrospective evaluation of 16 patients with arteriosclerosis obliterans who had undergone femoro-popliteal bypass surgery using an expanded polytetrafluoroethylene graft.  Patients received either cilostazol 150-200 mg/day or warfarin.  Graft patency rates at 1, 3 and 5 years were comparable in the 2 groups.[42]

Contraindications, Warnings, & Precautions

Cilostazol is contraindicated in patients with any form of congestive heart failure.  It also should not be used by patients with known or suspected hypersensitivity to cilostazol or other product ingredients (carboxymethylcellulose calcium, corn starch, hydroxypropyl methylcellulose, magnesium stearate and cellulose).[35] 

The black box warning in the product labeling reads: 

Cilostazol and several of its metabolites are inhibitors of phosphodiesterase III.  Several drugs with this pharmacologic effect have caused decreased survival compared to placebo in patients with class III-IV congestive heart failure. 
PLETAL is contraindicated in patients with congestive heart failure of any severity.

 In patients without congestive heart failure, the long-term effects of PDE III inhibitors (including cilostazol) are unknown.  Patients in the 3-6 month placebo-controlled trials of cilostazol were relatively stable (no recent myocardial infarction or strokes, no rest pain or other signs of rapidly progressing disease) and only 19 patients died (0.7% in the placebo group and 0.8% in the cilostazol group).  There are no data as to longer-term risk or risk in patients with more severe underlying heart disease.[35] 

Cilostazol is classified as Pregnancy Category C.  Animal studies did indicate a decrease in fetal weight and increased incidence of cardiovascular, renal and skeletal anomalies.[35] 

Cilostazol is excreted in the milk of animals.  It is unknown if it excreted in human milk.  The manufacturer recommends either the nursing or the drug be discontinued.[35]  

Safety and effectiveness of cilostazol in pediatric patients have not been established.[35] 

Adverse Reactions

The most common adverse effects are headache, diarrhea, abnormal stools (loose stools), palpitation and dizziness, with headache occurring most frequently (see Table 7).[73,78,79,84]  Discontinuation of therapy due to side effects was reported for 16% of cilostazol-treated patients compared to 9% of placebo-treated patients in clinical trials.[84]  Headaches were most frequently described as mild and responded to nonprescription analgesics.[79] 

The only adverse effects resulting in discontinuation of therapy in >3% of patients treated with cilostazol 50 or 100 mg twice daily was headache, which occurred with an incidence of 1.3%, 3.5%, and 0.3% in patients on cilostazol 50 mg twice daily, cilostazol 100 mg twice daily, or placebo, respectively.  Other frequent causes of discontinuation included palpitations and diarrhea, both 1.1% of cilostazol versus 0.1% for placebo.[35] 

Table 7: Adverse effects associated with cilostazol therapy.[35]

Adverse Effect

Cilostazol
50 mg twice daily
(n=303)

Cilostazol
100 mg twice daily
(n=998)

Placebo

(n=973)

Headache

27%

34%

14%

Infection

14%

10%

8%

Abnormal stools

12%

15%

4%

Diarrhea

12%

19%

7%

Rhinitis

12%

7%

5%

Peripheral edema

9%

7%

6%

Dizziness

9%

10%

6%

Pharyngitis

7%

10%

7%

Back pain

6%

7%

6%

Dyspepsia

6%

6%

4%

Nausea

6%

7%

6%

Palpitations

5%

10%

1%

Abdominal pain

4%

5%

3%

Tachycardia

4%

4%

1%

Vertigo

3%

1%

1%

Cough increased

3%

4%

3%

Flatulence

2%

3%

2%

Myalgia

2%

3%

2%

 

 The safety of cilostazol was examined through electrocardiogram (ECG) and Holter monitoring data.  ECG were obtained frequently throughout the Phase III studies.  Evaluation of the ECG parameters showed decreases in PR, QRS, and QT intervals, and an increase in heart rate of 5 and 7 beats per minute on average for the 50 mg twice daily and 100 mg twice daily doses of cilostazol, respectively.  The QTc, which is a function of the QT interval and heart rate, did not change for either dose of cilostazol.[35] 

The relative risk of death is 1.2.[35]  While this had a wide 95% confidence interval limit (0.5-3.1), it is still a matter of concern.  Animal studies have shown cardiovascular lesions, including endocardial hemorrhage, hemosiderin deposition and fibrosis in the left ventricle, hemorrhage in the right atrial wall, hemorrhage and necrosis of the smooth muscle in the wall of the coronary artery, intimal thickening of the coronary artery and coronary arteritis and periarteritis.[35] 

Pregnancy data are not currently available.  In animal studies, cilostazol was excreted in breast milk at concentrations of 41- 72% of blood concentrations.[74] 

Drug Interactions

Drugs that inhibit the CYP3A4 and CYP2C19 isozymes will decrease the clearance and increase the peak plasma concentrations of cilostazol or its metabolite.  Examples of CYP3A4 inhibitors are ketoconazole, itraconazole, erythromycin, diltiazem and grapefruit juice.  An example of a CYP2C19 inhibitor is omeprazole.[35,85,86]  Erythromycin increases the peak plasma concentration of cilostazol by 47% and the AUC by 73% and increases the AUC of the 4’-trans-hydroxy-cilostazol by 141%.  Diltiazem increases the peak plasma concentration by 53%.[35]  The impact of other CYP3A4 inhibitors has not been evaluated but is expected to increase the plasma levels of cilostazol and its metabolites.  Omeprazole does not affect the metabolism of cilostazol but does affect the elimination of the 3,4-dehydro-cilostazol metabolite.  The levels of this metabolite are increased by 69%.[35,85]  Phase 4 studies are required by the FDA to determine the effect of ketoconazole and grapefruit juice on the pharmacokinetics of cilostazol.[80] 

Aspirin plus cilostazol may further decrease platelet aggregation, but it has no clinically significant impact on bleeding time compared to aspirin alone.  Patients who received both drugs in the clinical trials did not have an increased incidence of hemorrhagic adverse effects.[35,87]  Whether a similar effect is seen with clopidogrel is unknown.  The company has been required to conduct a Phase 4 trial that enrolls patients receiving clopidogrel therapy to determine if there is an increased risk of bleeding.[80,88] 

Single dose and multiple dose administration with warfarin shows no pharmacokinetic or pharmacodynamic interactions.[35,89]  However, this combination should be used with caution until multiple dose studies are conducted. Based on the results of single dose administration studies, quinidine appear to be unaffected by cilostazol administration.[35,90]  Administration of cilostazol with lovastatin can produce a small decrease in cilostazol peak serum concentrations (14%) and area-under-the-curve (15%).  While the levels of lovastatin are unaffected by cilostazol, lovastatin's area-under-the-curve is increased by 1.6-fold.  And the area-under-the-curve of lovastatin's metabolites are increased by 1.7 and 2.0-fold.  The dose of lovastatin should be decreased when the two drugs are given together.[91] 

Table 8: Drug interactions of cilostazol with common pharmacologic therapies.[35,87,85,86,90,89,91]

Drug

Effects of coadministration

Aspirin (<325 mg qd)

No effect see in:

·        Prothrombin time

·        Activated partial thromboplastin time

·        Bleeding time

·        23-35% increase in inhibition of ADP-induced ex vivo platelet aggregation compared to aspirin alone

·        Effects of long-term coadministration in the general population are unknown

Erythromycin

·        Increased systemic exposure (AUC) of cilostazol (73%) and metabolites 4'-trans-hydroxy-cilostazol (141%)

·        Increased peak serum concentration of cilostazol (47%) and metabolite 4'-trans-hydroxy-cilostazol (29%)

·        Increased incidence of headache by 19%

Lovastatin

·        No clinical significant increases in plasma concentration of lovastatin and its hydroxyacid metabolite with single dose administration.

·        Multiple dose administration shows an increase in the systemic exposure (AUC) of lovastatin and its metabolites and a small decrease in cilostazol levels and absorption.

Omeprazole

·        Increased systemic exposure (AUC) of cilostazol (26%) and metabolite  3,4-dehydro-cilostazol (69%)

·        Increased peak serum concentration of cilostazol (18%) and metabolite  3,4-dehydro-cilostazol (29%)

Quinidine

No increase in plasma levels of cilostazol or its metabolites

Warfarin

No effect seen in:

·        Prothrombin time

·        Activated partial thromboplastin time

·        Bleeding time

·        Pharmacokinetics

Diltiazem

Increases the peak plasma concentration of cilostazol by 53%

Pentoxifylline

Unknown

Clopidogrel

Unknown

 

 Availability & Storage

Cilostazol is available as 50 mg and 100 mg tablets.  The 50-mg tablets are white, triangular, debossed with PLETAL 50, and provided in bottles of 60 tablets and hospital unit dose packs of 100 tablets.  The 100-mg tablets are white, round, debossed with PLETAL 100, and provided in bottles of 60 tablets and hospital unit dose packs of 100 tablets.[35] 

The tablets should be stored at room temperature (25°C or 77°F) with excursions permitted to 15-30°C and 59-86°F.[35]

Dosing

Cilostazol has been dosed at 100 mg twice daily in the treatment of intermittent claudication and in the treatment of ischemic symptoms such as ulcer, pain and cold sensation due to severe peripheral arterial disease.[56,79] 

The recommended adult dosage of cilostazol is 100 mg twice daily.  The tablet should be taken at least half an hour before or 2 hours after breakfast and dinner.[35]  No adjustment is necessary for renal impairment or mild hepatic impairment.[92,93]  Caution should be used when cilostazol is administered to patients with moderate or severe hepatic impairment.[93] 

A lower dose (50 mg twice daily) should be considered if the patient is receiving concurrent therapy with ketoconazole, itraconazole, erythromycin, diltiazem or omeprazole.[35,85,86]  The patient should also be instructed to avoid grapefruit juice.[35]  Safety and effectiveness studies have not been conducted in children.[35]

Patient Counseling

Cilostazol is used to improve blood flow and blood circulation in the legs.  It may take several weeks for the medicine to make a difference in how far you can walk without pain or discomfort.  In order for the cilostazol to work best, you must take it on a continuous basis along with the exercise program that has been suggested by your physician. 

Potential side effects that may occur while taking cilostazol are increased heart rate, palpitataions, diarrhea, abnormal stools, and headache.  Most of these side effects will go away during treatment, but if they continue or are bothersome you should contact your prescriber.  If you experience a rash or vomiting, you should check with your prescriber immediately. 

The patient should take their cilostazol twice a day, at least one half-hour before or two hours after breakfast and dinner.  Grapefruit juice can increase the amount of cilostazol in the blood and should not be used to take your cilostazol dose.  However, other citrus juices can be used.  If you miss a dose take it as soon as possible.  If it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. 

Copy of Pletal® Product Labeling

Copy of the Pletal® Patient Package Insert

PHARMACIST'S ROLE IN THE TREATMENT OF INTERMITTENT CLAUDICATION:

The pharmacist's has a very important role in the identification and treatment of intermittent claudication.  You may be the first health care professional that is contact by the patient about their difficult in walking.  This may be as a general question or as a question from the patient wondering if it is a side effect of a medication they are taking.  In this situation, you should consider providing the patient with the simple patient questionnaire that was discussed in the first portion of this program.

Examples of questions that could be include in questionnaire are:

The most critical role a pharmacist has in the care of the patient with intermittent claudication is helping with the patient's medication compliance.  If these medications are not taking on a continuous basis along with their exercise program, the patient may perceive no benefit or may not achieve their optimal performance.  The patient has need to understand when they start these medications, the maximum benefit may not be achieved for several weeks to months.  All medications should be given a minimum trial period of 3 months, unless the patient experiences intolerable side effects.

CONCLUSION: 

Intermittent claudication is pain in the legs that occurs with walking and resolves with rest.  Patients with intermittent claudication can usually walk only short distances and are therefore often unable to perform their daily activities.  Patients can typically walk only one-half block to four blocks before they must stop and rest.   About one-third of patients indicate that they have difficulty walking around their homes, and two-thirds indicate that they have difficulty walking 150 feet, whereas age-matched controls are essentially unlimited in the distance they can walk.

The primary treatment objective for patients with intermittent claudication is to improve their pain-free and maximal walking distances.  Treatment options include risk factor reduction, exercise rehabilitation, and pharmacologic therapy; surgical revascularization may be necessary if other therapies fail.

Pentoxifylline may be effective in some patients.  But the use of pentoxifylline has fallen over the past several years because of poor results. 

Cilostazol appears to produce moderate improvements in walking distance in patients with intermittent claudication, and may prove useful as an alternative to pentoxifylline in this indication.  Other drugs that have been used to treat this condition include pentoxifylline (Trental), cyclandelate (Cyclospasmol) and ticlopidine (Ticlid).  None of these drugs are miracle agents, and the improvements in walking distance seem small to healthy individuals.  However, for a person with intermittent claudication, these modest improvements can mean the difference between ambulation and risked mobility.  It may take up to 12 weeks of therapy before a beneficial effect is experienced.

Case Study #1
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Case Study #3
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